GLP-1 Based Combination Therapy for Obesity and Diabetes

Obesity and its comorbidities, such as type 2 diabetes, are major public health diseases in modern society. Despite the currently significant unmet needs of type 2 diabetes patients, effective and safe pharmacological treatments that deliver adequate weight loss and glucose control have not been discovered. Anorectic gut hormone, glucagon-like peptide 1 (GLP-1), is widely used to treat obesity and diabetes.1,2 GLP-1 is a type of incretin released from the L cells of the large intestine and distal ileum when nutrients contact the intestine. In rodents and humans, GLP-1 receptor (GLP-1R) is expressed in many tissues including α, β, and δ cells of the pancreatic islets, lung, heart, kidney, stomach, intestine, pituitary, skin, nodose ganglion neurons of the vagus nerve and several regions of the central nervous system including the hypothalamus and brainstem.3 The GLP-1 agonist, Exendin-4, has been shown to reduce food intake by slowing gastric emptying and increasing satiety.4–9 GLP-1 exhibits an anti-diabetic effect in addition to the above-mentioned anti-obesity effect. GLP-1 potentiates glucose-stimulated insulin secretion and enhances glucose homeostasis. GLP-1 agonists usually provide significant weight reduction and glucose improvement, but only a few patients achieve adequate weight/glucose control and often experience dose-limiting adverse effects such as nausea and risk of pancreatitis. Therefore, many researchers pursue novel therapeutics that combine GLP-1/GLP-1 agonists with other peptides such as gastric inhibitory polypeptide (GIP), glucagon and peptide YY (PYY) (Table 1). Effective combination drugs may produce synergistic effects by targeting multi-organ mechanisms (Fig. 1). In this editorial, we discuss the preclinical and clinical studies on GLP-1-based combination therapies for obesity and diabetes. Open in a separate window Figure 1 Metabolic actions of GLP-1-based combination therapy on major organs (BAT, WAT, circulation, brain, liver and pancreas). GIP, gastric inhibitory polypeptide; PYY, peptide YY; GLP-1, glucagon-like peptide 1; BAT, brown adipose tissue; WAT, white adipose tissue.